Culprits in life-threatening clotting disorder uncovered
By ANISaturday, December 4, 2010
WASHINGTON - Individuals with a potentially life-threatening condition predisposing them to blood clots, or thrombosis, might someday receive therapy to prevent the condition, thanks to new findings by UT Southwestern Medical Center researchers.
The findings offer new clues into the mechanisms underlying antiphospholipid syndrome (APS).
“Patients with APS have circulating antibodies that cause exaggerated thrombosis. The longstanding mystery has been how these antibodies initiate the clotting,” said Philip Shaul, professor of pediatrics and senior co-author of the study.
For the study, the researchers first examined the direct actions of APS antibodies on cultured endothelial cells, which line the inside of blood vessels.
They discovered that the thrombosis-inducing antibodies recognize a protein called Beta2-Glycoprotein I on the endothelial cell surface that then interacts with a second protein, apolipoprotein E receptor 2 (apoER2).
ApoER2 ultimately inactivates the enzyme that produces the antithrombotic molecule nitric oxide. The decrease in nitric oxide causes both white blood cells and platelets to bind to the endothelium, initiating the thrombosis.
The study also found that in contrast to normal mice, mice genetically engineered to lack apoER2 are completely protected from developing thrombosis when they are given APS antibodies collected from individuals with the syndrome.
“Patients with thrombosis often require lifelong anti-coagulation therapy. The problem with this approach is that the anti-coagulation can be ineffective, and there are multiple potential serious complications related to bleeding. It makes much more sense to develop new therapies that target the underlying disease mechanism,” he said.
Chieko Mineo, senior co-author of the study, said the findings are particularly important for pregnant women with APS because they are at high risk of miscarriage and preterm birth.
The findings were reported in the Journal of Clinical Investigation. (ANI)
